Activated protein C resistance as an additional risk factor for thrombosis in protein C-deficient families

Heterozygous protein C deficiency is associated with an increased risk for thrombosis. This association is restricted to a minority of protein C-deficient families, which have been defined as clinically dominant protein C-deficient. In contrast, in the clinically recessive protein C- deficient families, only the homozygous family members are (severely) affected. One possible explanation for this difference in thrombotic risk between families may be the presence of a second hereditary risk factor. A good candidate for this second risk factor is the recently identified resistance to activated protein C (APC). APC resistance, which is associated with a mutation in the FV gene (FV Leiden), is a common and strong risk factor for thrombosis. We show here that the prevalence of the FV Leiden mutation is high among symptomatic protein C-deficient probands (19%). In 6 clinically dominant protein C- deficient families, the segregation of the FV Leiden mutation and the protein C gene mutation was studied. A thrombotic episode had been experienced by 73% of the family members having both the protein C gene mutation and the FV Leiden mutation. In contrast, respectively, 31% and 13% of the family members having either the protein C gene mutation or the FV Leiden mutation had experienced a thrombotic episode. Moreover, the result of a two locus linkage analysis support the assumption that the FV gene and the protein C gene are the two trait loci responsible for the thrombophilia. These results indicate that carriers of both gene defects have an increased risk for thrombosis compared with related carriers of the single defect.     

Fetal hemoglobin synthesis in erythroid cultures in hereditary persistence of fetal hemoglobin and beta o-thalassemia

To determine whether hemoglobin regulation is normal in diseases affecting beta-globin gene expression, globin synthesis was examined in members of a family of a patient with hereditary persistence of fetal hemoglobin/beta o-thalassemia (HPFH/beta o-thal). The HPFH defect is the Ghanian type II, with a deletion from psi beta 1 to at least 20 kb 3' to beta. The beta o-thal gene has the haplotype II restriction enzyme pattern and has the beta 39 nonsense mutation. Erythroid colonies from blood BFU-E were radiolabeled, and globin chains were separated by gel electrophoresis. Colonies from the beta o-thal heterozygote had non-alpha/alpha ratios more balanced than in the reticulocytes. Gamma synthesis was 11% of non-alpha, which is higher than in reticulocytes, but within the range seen in normal adult colonies. Both HPFH heterozygotes produced 20%-30% gamma in erythroid colonies as well as reticulocytes, although non-alpha/alpha was more balanced in the colonies. The HPFH/beta o-thal patient produced 100% gamma in reticulocytes and in colonies. G gamma and gamma-synthetic proportions were not correlated at the individual colony level in the heterozygotes, suggesting that they had "adult" and not "fetal" progenitor cells. The Hb expression of these adult progenitors is presumably modulated normally in vivo in beta o-thal, but the normal decrease in HbF production does not occur in gene deletion HPFH.     

Fetal erythropoiesis following bone marrow transplantation

"Fetal" erythrocytes are present in older children and certain adults with hematologic disorders. To determine if regenerating bone marrow produces such cells, we examined the blood of seven allogeneic bone marrow transplant recipients. Six patients were engrafted with donor cells, while on e patients recovered autologous bone marrow after rejection of a marrow transplant. All seven patients had fetal hemoglobin levels of up to 10% by 100 days after transplant. In three patients, the Ggamma to Agamma ratio in the fetal hemoglobin was "newborn", while in one it was "adult". Gamma chain synthesis in blood and bone marrow never exceeded 20% of total non-alpha globin synthesis. The fetal hemoglobin was heterogeneously distributed in the cells. High titer i antigen also appeared. All fetal characteristics declined by 200 days. Erythropoiesis during bone marrow recovery appears to be associated with an accelerated, albeit partial, recapitulation of ontogeny.     

Ulcer healing properties of different extracts of Origanum majorana in streptozotocin-nicotinamide induced diabetic rats

ObjectiveThe aim of the present investigation was to evaluate the ulcer healing properties of different extracts of Origannum majorana, viz., hydrodistilled volatile oil (OMO), methanolic (OMM) and aqueous extract (OMW) in streptozotocin-nicotinamide induced diabetic rats.MethodsAll the extracts were administered in different doses (100, 200 and 400 mg/kg, p.o.) to investigate the ulcer healing potential. Streptozotocin (STZ; 65 mg/kg, i.p.) along with nicotinamide (120 mg/kg, i.p.) was used to induce non-insulin dependent diabetes mellitus in rats. Aspirin (200 mg/kg, i.p.) was administered for initial 7 d to induce gastric ulcerations in the diabetic rats. Various biochemical markers of blood and tissue origin were estimated to compare the ulcer healing potential of these extracts.ResultsThe OMO and OMM exhibited dose dependent significant (P<0.01) ulcer healing property than the OMW. Additionally, the antidiabetic property of OMO and OMM was better than OMW.ConclusionThe OMO and OMM of Origanum majorana leaves can prove to be beneficial in the concomitant treatment of gastric ulcers and diabetes.     

De novo minimal change disease

Beyond the acute posttransplantation period, glomerular causes of proteinuria in the renal allograft include recurrent glomerulopathy, transplant-associated entities, and de novo disease. We present a case of de novo minimal change disease with reversible acute renal failure occurring 2.5 years posttransplantation in a 56-year-old man. The cause of end-stage renal disease in the native kidney was membranous glomerulopathy. De novo minimal change disease in the renal allograft is an extremely rare entity requiring stringent clinical-pathological criteria for diagnosis. Many of the cases previously reported as de novo minimal change disease fail to meet these criteria. We review the eight reported cases that appear to fulfill a strict definition of minimal change disease in the context of the current report.     

The role of germline polymorphisms in the T-cell receptor in susceptibility to ankylosing spondylitis

The role of germline polymorphisms of the T-cell receptor A/D and B loci in susceptibility to ankylosing spondylitis was investigated by linkage studies using microsatellite markers in 215 affected sibling pairs. The presence of a significant susceptibility gene (lambda > or = 1.6) at the TCRA/D locus was excluded (LOD score < -2.0). At the TCRB locus, there was weak evidence of the presence of a susceptibility gene (P = 0.01, LOD score 1.1). Further family studies will be required to determine whether this is a true or false-positive finding. It is unlikely that either the TCRA/D or TCRB loci contain genes responsible for more than a moderate proportion of the non-MHC genetic susceptibility to ankylosing spondylitis.      

Determinants of Achieving Early Blood Pressure Control with Monotherapy in a Primary Care Setting

This study sought to identify the determinants of early blood pressure (BP) control associated with monotherapy in hypertensive individuals being managed in the primary care setting. The Valsartan Intensified Primary Care Reduction of Blood Pressure (VIPER‐BP) study, was a multicenter, randomized controlled trial of an intensive approach to BP management. During a standardized run‐in, 2185 participants commenced monotherapy (valsartan 80 mg/d) for 14 to 28 days. A total of 1978 participants aged 59±12 years (60% men) completed the run‐in phase. Of these, 15.1%, 43.5%, and 41.4% participants had an initial BP target of ≤125/75, 130/80, and 140/90 mm Hg, respectively. A total of 416 of 2185 participants (19.0%) subsequently achieved their individual BP target during run‐in with a mean BP change of −22.6±12.1/−12.9±8.2 mm Hg vs −4.2±16.2/−3.0±9.6 mm Hg for the rest (P<.001). These early responders were more likely to be women (adjusted odds ratio, 1.41; 95% confidence interval, 1.10–1.80), had lower BP at baseline, were less likely to have been treated previously (or for less time), and had a less stringent BP target. An initial period of monotherapy achieved BP control in a high proportion of hypertensive individuals with key groups (including women and de novo cases) more likely to show an early BP response.

Elevated blood pressure (BP), or hypertension, represents one of the most preventable and yet seemingly intractable contributors to cardiovascular disease (CVD). Overall, hypertension is estimated to contribute to around 30% to 40% of all‐cause or CVD‐related case fatalities in high‐income countries such as the United States.¹ A critical factor in this phenomenon is the high proportion of identified individuals with hypertension who remain above their BP target and therefore at sustained elevated risk for a primary or secondary cardiovascular event.² Given the volume of cases, the majority of such individuals are managed in the primary care environment using office‐based measurements of BP, although there is increasing focus on 24‐hour ambulatory monitoring and home‐based monitoring³ to minimize potential white‐coat or masked hypertension and inappropriate or foregone treatment.⁴ In Australia, nearly 1 in 10 primary care encounters is related to hypertension⁵—more than any other single contributor to health care activity. As indicated, despite an array of effective pharmacologic agents, particularly when applied in combination (preferably a single pill to encourage treatment adherence), BP control rates remain suboptimal.Beyond the application of pharmacotherapy, there is strong evidence, including a Cochrane review of the literature, that more intensive and structured management in the primary care setting will significantly improve BP control rates.⁶ We therefore conducted the multicenter, randomized Valsartan Intensified Primary Care Reduction of Blood Pressure (VIPER‐BP) study⁷ to test the clinical effectiveness and overall safety of a more intensive and structured approach to optimizing BP control in a group of individuals with persistently high BP levels in primary care. During the randomized component of comparing the VIPER‐BP intervention (n=1038) with an enhanced form of usual care (n=524), the primary endpoint (individual risk‐based BP target) was achieved in 36.2% vs 27.4% of participants, respectively (adjusted relative risk 1.28 in favor of the intervention; P=.001) and the classical BP target of ≤140/90 mm Hg in 63.5% vs 54.0% of participants (adjusted relative risk 1.18 in favor of the intervention; P<.001).⁸ However, prior to randomization, a total of 2185 participants were exposed to a standardized run‐in period comprising clinical profiling and low‐dose angiotensin receptor blockers (ARBs) for 28 days.     

CHF5074, a novel γ-secretase modulator,attenuates brain β-amyloid pathology and learning deficit in a mouse model of Alzheimer's disease

Background and purpose:

We evaluated the effects of 1-(3′,4′-dichloro-2-fluoro[1,1′-biphenyl]-4-yl)-cyclopropanecarboxylic acid (CHF5074), a new γ-secretase modulator, on brain β-amyloid pathology and spatial memory in transgenic mice expressing the Swedish and London mutations of human amyloid precursor protein (hAPP).

Experimental approach:

Sixty 6-month-old hAPP mice were treated for 6 months with CHF5074 or ibuprofen (375 ppm in the diet) or standard diet. Twenty-one wild-type mice received standard diet.

Key results:

Compared with transgenic controls, CHF5074 treatment significantly reduced the area occupied by plaques in cortex (P = 0.003) and hippocampus (P = 0.004). The number of plaques were also reduced by CHF5074 in both cortex (P = 0.022) and hippocampus (P = 0.005). Plaque-associated microglia in CHF5074-treated animals was lower than in transgenic controls in cortex (P = 0.008) and hippocampus (P = 0.002). Ibuprofen treatment significantly reduced microglia area in cortex and hippocampus but not β-amyloid burden. On the last day of the Morris water maze, transgenic controls performed significantly worse than the non-transgenic animals and the CHF5074-treated transgenic mice, on the swimming path to reach the hidden platform. Ibuprofen-treated animals did not perform significantly better than transgenic controls.

Conclusions and implications:

Chronic CHF5074 treatment reduced brain β-amyloid burden, associated microglia inflammation and attenuated spatial memory deficit in hAPP mice. This novel γ-secretase modulator is a promising therapeutic agent for Alzheimer''s disease.